Antitumor dibenzofluorene derivatives

ABSTRACT

Dibenzofluorene derivatives having a formula selected from the group consisting of                    
     and salts thereof have antitumor activity. At least one of R 1 -R 13  in formula (I) or R 1 -R 12  in formula (II) is —R 14 Z. R 14  is a substituted or unsubstituted amino or amido group having from 1-12 carbon atoms, and Z is a substituted or unsubstituted heterocyclic group having from 1-12 carbon atoms. The remainder of R 1 -R 13  in formula (I) or R 1 -R 12  in formula (II) are independently selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted amino or amido groups having from 1-12 carbon atoms, and alkyl groups having 1-12 carbon atoms.

This is a division of prior application Ser. No. 09/634,102, filed Aug.8, 2000, which is a division of prior application Ser. No. 09/203,650,filed Dec. 1, 1998 now U.S. Pat. No. 6,184,224.

BACKGROUND OF THE INVENTION

The present invention relates to compounds having antitumor activity.The invention also relates to pharmaceutical compositions that containone or more of those compounds, methods of using the compounds toinhibit tumor growth in mammals, and methods of preparing the compounds.

Many thousands of people are diagnosed with cancer each year, andalthough great advances have been made in cancer therapy, the existingtreatments are not successful in many cases. Among the problems withexisting therapies are (1) anticancer drugs administered to patientsoften have toxic effects on non-cancerous cells in the patient's body,(2) cancerous cells whose growth can be inhibited by certain drugssometimes become resistant to those drugs, and (3) some cancers cannotbe effectively treated with a single drug, and sometimes not even with acombination of different anticancer drugs. A long-standing need existsfor new anticancer drugs that have one or more of the followingcharacteristics: (1) ability to inhibit the growth of cancerous cells.(2) acceptable levels of toxicity to non-cancerous cells, (3)effectiveness against cancerous cells that are resistant to other drugs,and (4) a different mechanism of action than existing drugs, so thatwhen the new drug is used in combination with an existing drug, thelikelihood of the cancer cells developing cross-resistance is reduced.

SUMMARY OF THE INVENTION

The present invention concerns compounds having a formula selected fromthe group consisting of

or salts thereof. In the above formulas, at least one of R₁-R₁₃ informula (I) or at least one of R₁-R₁₂ in formula (II) is —R₁₄Z. R₁₄ is asubstituted amino or amido group preferably having from 1-12 carbonatoms. Z is a substituted or unsubstituted heterocyclic group preferablyhaving from 1-12 carbon atoms. The remainder of R₁-R₁₃ in formula (I) orR₁-R₁₂ in formula (II) are independently selected from the groupconsisting of hydrogen, hydroxyl, halogen, nitro, substituted orunsubstituted amino or amido groups preferably having from 1-12 carbonatoms, and alkyl groups preferably having from 1-12 carbon atoms.

As mentioned above, salts of the compounds (I) and (II) are part of thepresent invention. Examples of suitable salts include but are notlimited to the hydrochloride, iodide, and methane sulfonate salts.

In one embodiment of the invention where the compound has formula I, R₁₁is —R₁₄Z, and R₁-R₁₀ and R₁₂-R₁₃ are independently hydrogen, hydroxyl,halogen, nitro, substituted or unsubstituted amino or amido having from1-12 carbon atoms, or alkyl having 1-12 carbon atoms

In another embodiment of the invention where the compound has formulaII, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂ are independently hydrogen,hydroxyl, halogen, nitro, substituted or unsubstituted amino or amidohaving from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.

R₁₄ preferably has the formula —NHR₁₅—, where R₁₅ is a substituted orunsubstituted aliphatic group having from 2-6 carbon atoms. R₁₅preferably is selected from the group consisting of —CO(CH₂)_(n)CO—,—(CH₂)_(m)—, and —CO(CH₂)_(q)CHCH(CH₂)_(r)CO—, where n, m, q, and r areindependently a number from 0-6. In one preferred embodiment of theinvention, n is from 1-4, m is from 2-6, q is from 0-2, and r is from0-2. Z preferably is selected from the group consisting of piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, hydroxyethylpiperazinyl, aminoethyl piperazinyl, and aminomethyldihydroxypiperidinyl.

Another aspect of the present invention is pharmaceutical compositionsthat comprise a compound as described above and a pharmaceuticallyacceptable carrier. Yet another aspect of the present invention is amethod of inhibiting the growth of tumor cells, in which atumor-inhibitory amount of a compound as described above is administeredto a mammal.

Another aspect of the present invention is a method of synthesizing acyclic hydrocarbon and keto compound. The method comprises the step ofreacting a cyclic hydrocarbon compound that comprises at least two ringswith a metal bismuthate in the presence of an acid. The metal bismuthatecan be for example an alkali metal bismuthate such as sodium bismuthate.As another example, it can be zinc bismuthate. In certain embodiments ofthis method, the acid can be an organic acid such as acetic acid or amineral acid such as sulfuric acid. Optionally the reaction can takeplace in the presence of an organic solvent, such as acetone. The cyclichydrocarbon reactant preferably comprises from 10-50 carbon atoms.

The compounds and compositions of the present invention are useful incancer therapy, either by themselves or in combination with otherantitumor chemotherapy or radiation therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a synthesis scheme that is described in Example 1.

FIGS. 2-4 depict synthesis schemes that are described in Example 2.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Polycyclic aromatic compounds are widely distributed in nature and areconsidered to be among the significant environmental carcinogens [1].Previously, considerable research has been directed towards thesynthesis of the polycyclic ring systems [2] and examination of theirmetabolic activation within target cells. Several hypotheses [3] havebeen proposed to establish the correlations between the structure ofthese metabolites, their cellular interactions and carcinogenicity.Eventually, most of the polycyclic metabolic products which act ascarcinogens, intercalate with or bind covalently to DNA. Examination ofseveral frequently used antitumor agents revealed two common structuralfeatures [4]: they have a planar ring system and a basic side chain. Itcould be predicted, therefore, that in addition to other cellularinteractions these compounds would first demonstrate a stronginteraction with the lipid domains of the plasma membranes and othermembranes within the cell [5].

In some instances, antitumoral, DNA-intercalating drugs have been shownto interact with cell membranes and in some cases have demonstratedantitumor activities without further penetrating the cell structure.This then would put them in a class of drugs that have been calledgenerically membrane stabilizing agents (MSA) [6]. These are agentswhich increase membrane stability against various stressors and often athigher concentration induce membrane destabilization. For example, theymay act as anti-hemolytic agents at lower concentrations and causehemolysis at higher concentrations. In order to determine the importanceof these primary interactions with the plasma membrane of tumor cells inantitumor effects, we undertook an exploratory synthetic and biologicalevaluation of unique polycyclic aromatic compounds. This was based onour belief that the potential use of such compounds as antitumor agentshas not been systematically explored [7], especially when specificmodification is applied to enhance the membrane interaction as theprimary effector of antitumor activity. On this basis, we began thissystematic analysis by synthesizing a number of dibenzofluorenederivatives and studied their biological effects in vitro on a panel ofhuman tumor cell lines.

A number of compounds of the present invention have been prepared, andare listed in Table 1.

TABLE 1 Compound No. Compound Name Tx-37N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-38N-[11′-(13′H-Dibenzo[a,g]-fluorenyl]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide Tx-47N-[11′-(13′H-Dibenzo[a,g]-fluorenyl]-4-(4′N methyl-piperazinyl)-but-2-ene-1,4-dicarboxiamide Tx-48N-[11′-13′H-Dibenzo[a,g]-fluorenyl]-4-(1′-piperidinyl)-but-2-ene-1,4-dicarboxiamide Tx-49N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl- piperazinylhydrochloride)-butane-1,4-dicarboxiamide Tx-50N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-51N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide Tx-66N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(4′N-methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-67N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide Tx-68N-[2′-(9′H-fluorenyl)]-4-(4′N methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-69N-[2′-(9′H-fluorenyl)]-4-(1′-piperidinyl)-butane-1,4- dicarboxiamide

Methods for synthesizing the compounds of the present invention aredescribed in the examples below. Therapeutic compositions containingthese compounds will preferably also include one or morepharmaceutically acceptable carriers, such as saline solution, and mayalso include one or more pharmaceutically acceptable excipients and/oradditional biologically active substances.

The compounds of the present invention can be used in methods ofinhibiting the growth of tumor cells in mammals, particularly in humans.Specific human malignancies for which these compounds should be usefulinclude breast, colon, ovarian, and prostate cancers, melanoma,leukemia/lymphomas, and possibly others as well. The compounds areadministered to a mammal in an amount effective to inhibit the growth oftumor cells in the mammal. The administration can suitably be parenteraland by intravenous, intraarterial, intramuscular, intralymphatic,intraperitoneal, subcutaneous, intrapleural, or intrathecal injection.Such administration is preferably repeated on a timed schedule untiltumor regression or disappearance has been achieved, and may be used inconjunction with other forms of tumor therapy such as surgery orchemotherapy with different agents. A compound of the present inventionis preferably administered in a dose that is between approximately 0.01and 100 mg/kg of body weight of the mammalian subject.

The present invention can be further understood from the followingexamples.

EXAMPLE 1

This example relates to synthesis of polycyclic aromatic ketones.

The oxidizing power of sodium bismuthate in acid media is proved by thefacile conversion of bivalent manganese salts to heptavalent manganese.[8] In comparison to other, common oxidizing agents, the use of thisreagent in synthetic organic chemistry has not been extensivelyexplored. Rigby [9] demonstrated the cleavage of vicinal diols and theconversion of acyloins to α-diketones by sodium bismuthate. This reagentwas also used for the oxidation of phenols [10], olefins [11] andα-ketols. [12] Recently, a few other bismuth derivatives were developedfor the oxidation of various functional groups. [13]

Oxidation of benzylic methylenes to the ketones by DDQ [14], PCC [15],CrO₃ [16], tBuOOH [17], tetrapyridinesilver peroxydisulfate [18] isknown in the literature. Recently, Harvey et al [19] reported a newoxidation method with n-BuLi in the presence of molecular oxygen.Although this method is attractive, it has several limitations. Forexample, oxidation of some structurally similar benzylic compounds couldnot be achieved by this method. Dimer formation in strong basic mediawas observed and mixtures of products were formed in some cases. Mostimportantly, extreme precaution has to be taken to get successfulresults as the method requires absolutely dry and inert media.

We have now oxidized benzylic methylenes to ketones under refluxcondition. using sodium bismuthate in acetic acid. As shown in FIG. 1,commercially available tetralin (1), diphenylmethane (5), 9-10dihydroanthracene (3), dibenzosuberane (9) flourene (7a) and2-nitroflourene (7b ) were readily converted to the respective ketones2, 6, 4, 8a, 8b and 10 by sodium bismuthate in acetic acid. We selectedtwo synthetic compounds, 2,3-benzo fluorene (11) and13H-dibenzo[a,g]fluorene (13) reported by Harvey et al [14] for theoxidation study and produced the ketones 12 and 14 in good yield. Thepresence of acetic acid is required for the completion of the reaction.We found that the progress of the reaction became very slow when carriedout without acetic acid. However, use of 10% sulfuric acid did notchange the reaction time that was observed with acetic acid. In order tokeep the reactants in contact with the oxidizing agent, acetone wasadded as a co-solvent.

Oxidation of 1, 5, 7, 9, 11 and 13 produced monoketones 2, 6, 8, 10, 12,and 14 in 50-90% yield. The presence of the diketone was not observed inthe crude product while compound 3 produced a diketone 4 in 72% yield.No side products such as hydroxy, acetates, quinones or dicarboxylicacid were observed during this oxidation.

The mechanism of the sodium bismuthate induced oxidation is not firmlyestablished. Oxidation of phenols by sodium bismuthate in neutralaromatic solvent has been shown to proceed by one-electron [10(e)](through a radical intermediate) oxidation. Similar reaction in thepresence of acetic acid as the solvent is believed to occur through atwo-electron [10(f)] (carbonium ion) oxidation process. The suggestedmechanism has a close similarity to the chromic acid [20] mediatedbenzylic oxidation. Thus, we hypothesize that our acid-catalyzed sodiumbismuthate induced oxidation of benzylic methylenes may follow one ofthe processes mentioned above.

A representative procedure is as follows:

To the starting methylene compound (20 mmol) in acetic acid (4 mL, 50%)and acetone (2 mL), was added sodium bismuthate (80 mmol) and themixture was heated to reflux under an argon atmosphere. At the end ofreaction as indicated by TLC the mixture was filtered through a pad ofcelite and diluted with water (10 mL). The mixture was extracted withmethylene chloride (3×20 mL). The combined organic layer was washed withsodium bicarbonate solution (3×10 mL, 10%), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresultant crude product was purified by column chromatography. Allproducts have been characterized through a comparison of mp, TLC and NMRwith authentic compounds.

EXAMPLE 2

This example concerns synthesis of dibenzofluorene derivatives.

We have developed a novel oxidation method for the conversion ofbenzylic methylenes to benzylic ketones in polycyclic systems by sodiumbismuthate. Thus, as shown in FIG. 2, pentacyclic dibenzofluorene 101was oxidized to the dibenzofluorenone 102 in good yield.

We have also shown a facile reduction of the polycyclic aromatic nitrocompounds to polycyclic aromatic amines (for example, 3 to 4) bysamarium metal in the presence of catalytic amounts of iodine (see FIG.3).

Using these two methods, we became interested in examining theanti-tumor effects of structurally complex, angular dibenzofluorene[a,g] polycyclic systems with a very reactive bridged methylene group.We believe that a bridged unit in the polycyclic aromatic system couldplay an important role as this can form cation, anion and radicalintermediates. This example describes the nitration study of the 13-Hdibenzofluorene (101) and structure-activity relationship studies ofseveral 13-unsubstituted and 13-substituted diamides (110, 111 and 112).

We prepared pentacyclic dibenzo[a,g]fluorene (110) in 20% yield byfollowing the method reported by Harvey [21]. Functionalization ofbenzene and naphthalene derivatives by electrophilic reaction [22] isroutine organic chemistry. The orientation of the electrophile in suchmonocyclic or bicyclic derivatives is predictable. Similar substitutionreaction in polycyclic aromatic system is extremely difficult and thesite of attack does not follow any known orientation rule. In fact, verylittle is known about the electrophilic substitution reaction inpolycyclic aromatic system [23].

We planned to link a 4-carbon chain side chain with a heterocyclic baseat the end to the aromatic ring through nitrogen [24]. Therefore, ourtask was to prepare amino dibenzofluorene 106 for the subsequentderivatization. Towards this goal, we reacted the ketone 102 with nitricacid in acetic acid under different conditions and failed to get anydesired nitro derivative. However, the hydrocarbon 101 produced a singlenitro compound 105 with nitric acid-acetic acid at 0-5° C. in 80% yield.(See FIG. 2.) The location of the nitro group in the aromatic system wasdetermined by nmr spectra. The nmr spectrum (400 MHz) of the knownhydrocarbon 101 was taken. Based on the homonuclear decoupling and COSYnmr studies, all the protons in 101 were assigned as follows: (400 MHz,CDCl₃)δ: 8.81 (d, 1H, J=8.46 Hz, H₇), 8.50 (d, 1H, J=8.68 Hz, H₆), 8.02(d, J=8.22 Hz, H₁), 7.89-7.96 (m, 3H, H₄, H₅, H₁₀), 7.70 and 7.79 (2H,ABq, J=8.23 Hz, H₁₁, H₁₂), 7.60-7.65 (m, 1H, H₈), 7.45-7.54 (m, 3H, H₂,H₃, H₉). These assignments were supported by the data reported by Joneset al [25]. The nmr spectrum of the nitro compound 105 revealed theabsence of the AB quartet which was present in 101. The spectrum of 105showed a new singlet at δ8.39 and a new doublet at δ8.44 (J=8.75 Hz ).We eliminated positions C₁, C₄, C₇ and C₁₀ for the nitro group becauseof the singlet at δ8.44. The positions C₅, C₆, C₈ and C₉ were eliminatedbased on the homonuclear decoupling and COSY experiment. The region(δ7.5-7.6) of the hydrocarbon 101 remained unaffected in 105 clearlyruled out positions C₂ and C₃ for the nitro group in 105. We eliminatedposition C₁₂ because of the downfield doublet at δ8.44. The ¹³C nmrspectrum of 105 showed the presence of nine quaternary carbons. Thesignal at δ123.58 due to the C₁₁ carbon (verified by HETCOR study) wasnot present in the spectrum of 105. A new peak at δ145.24 appearedbecause of the nitro group. Thus, we assigned C₁₁ as the site of thenitro group in 105 based on extensive nmr study.

Reduction of the nitro compound 105 to the amino compound 106 wascarried out by Pd—C (10%)-ammonium formate [26], samarium-iodine andPd—C (10%)-hydrazine hydrate [27]. We found hydrazine hydrate and Pd/C(10%) gave the best results.

Our next task was to prepare the side chains 109 and to couple them tothe amine 106. (See FIG. 4.) The acid 108 was prepared by refluxingsuccinic anhydride (107) with piperidine (108a) and N-methylpiperazine(108b) The amine 106 was then condensed with the side chains 109 bymixed anhydride method. [28]

The desired diamides 110 were isolated by column chromatography. Thebenzylic methylene group in 110 was oxidized by molecular oxygen [29] toget the ketone 111 which was subsequently reduced to the alcohol 112.All new compounds gave satisfactory spectral data.

The compounds of this example (see FIGS. 2, 3, and 4) correlate to thelisting of compounds by Tx number in Table 1 as follows:

Compound Compound Tx No. 110a Tx-38 110b Tx-37 111a Tx-51 111b Tx-50112a Tx-67 112b Tx-66

EXAMPLE 3

Dibenzofluorene in Vitro Cytotoxicity Testing

Every dibenzofluorene derivative was tested, as will be described below,against six to eight cultured, tumor cell lines of human and/or animalorigin, at least half of which were selected from the NCI panel of testtumors. In each experiment, Adriamycin (ADR) was used as a maximallypositive control. Subsequent to our determination that thedibenzofluorene derivative Tx-37 demonstrated consistent, highlypositive effects, it was also included in the panel of test agents inevery experiment where dibenzofluorene derivatives were tested.

In Vitro Cytotoxicity Determinations

Data are IC₅₀ values (MTT assay) reported as μg/ml for 72 hourscontinuous exposure to the drug. Drugs were prepared in DMSO:PEG300(1:1). Further, dilutions were made in a cell culture medium with fetalbovine serum.

Test Tumor Lines BRO human melanoma HT-29 human colon adenocarcinomaP388/0 murine lymphatic leukemia MCF-7 human breast carcinoma HL-60human promyelocytic leukemia OVCAR 3 human ovarian carcinoma

Additional tumor lines against which the drugs were tested in certainseries included L1210 (leukemia), PC3 (prostate) and several others.

Compounds were evaluated for solubility characteristics in vehicleswhich would be appropriate for use in cell culture. The compounds wereadded to the cell lines under continuous culture for 72 hours.Inhibition of growth relative to control cell culture was determined bythe MTT method at the end of 72 hours. This is a test of the relativeability of a compound to inhibit cell growth not survival. However,inhibition of growth may reflect cell death and/or cytostasis.

Summarized results of the in vitro cytotoxicity testing, specificallyaverage IC₅₀ values for the various tumor lines, are given in Table 2.

TABLE 2 # Agent Runs P388/0 BRO HT-29 MCF-7 OVCAR-3 HL-60 Tx-37 5 2.01.8 1.9 3.0 1.9 1.6 Tx-38 3 42.9 46.4 34.4 22.8 39.5 14.9 Tx-47 1 15.41.2 16.7 20.2 1.1 1.2 Tx-48 1 71.5 22.6 52.2 18.3 23.4 30.1 Tx-49 1 3.12.5 2.5 5.7 2.8 2.5 Tx-50 2 3.7 11.2 10.0 18.1 6.6 4.0 Tx-51 1 55.4 47.265.1 27.0 16.2 32.0 Tx-66 1 2.1 6.0 5.9 4.2 2.0 Tx-67 1 9.2 14.7 8.9 8.85.6 Tx-68 1 41 7 18.2 31.7 Tx-69 1 41.5 28.9 52.6

An IC₅₀ value above 50 μg/ml indicates that there was insufficientcytotoxicity of the compound to achieve a 50% inhibition of cell growthat 50 μg/ml. In some cases, we observed cytotoxicity at 100 μg/ml butfew of the drugs are readily soluble at this concentration and the dataare not reliable.

ADR invariably produced the described anti-tumor effect against alltumor lines at concentrations lower than 1 μg/ml of culture media. Theeffect of the Tx-compounds was divided into five activity groups asdescribed below. In all cases, if activity against a single tumor linediffered radically from that against all others, notation was made ofthis specificity but the agent was grouped as determined by the majorityof the results.

Group A. These agents were effective against all tumor lines atconcentrations under 5 μg/ml. Some of these compounds were effective atless than 1 log difference from the activity of ADR.

Group B. These agents were effective against all tumor lines at lessthan 10 μg/ml.

Group C. These agents were effective against one-third to one-half ofall tumor lines tested at levels less than 10 μg/ml.

Group D. These agents were effective against one or two of the six toeight tumor lines tested at concentrations of less than 10 μg/ml.

Group E. These agents produced some anti-tumor effect at doses above 10μg/ml but less than 20 μg/ml.

Group F. These agents were “effective” against some tumor lines above 20μg/ml but often demonstrated no anti-tumor effect.

TABLE 3 GROUP A Tx-37 Tx-49 Tx-66 GROUP B Tx-50 Tx-67 GROUP C Tx-47GROUP E Tx-68 GROUP F Tx-38 Tx-48 Tx-51 Tx-69

In summary of these findings, the most active compound produced in thisseries was Tx-37, the dibenzofluorene molecule with a terminal N-methylpiperazine heterocyclic ring. While the hydrochloride salt (Tx-49) orthe addition of a hydroxyl moiety at position 13 (Tx-66), produced minorchange in the activity, the substitution of a ketone moiety at position13 (Tx-50) produced a slight diminution in activity. The insertion of anunsaturated bond in the alkyl chain at Tx-37 (Tx-47) reduced itsactivity significantly.

Tx-38 with a terminal piperidine heterocyclic ring demonstrated nosignificant anti-tumor activity and the insertion of an unsaturated bondin this molecule produced little or no change (Tx-48). However, theaddition of the hydroxyl moiety at position 13, which caused minorchange in Tx-37, greatly increased the activity of Tx-38 (Tx-67).

As we have reported in other compounds based on other polycyclic ringstructures, those that terminate in a N-methyl piperazine ring againdemonstrated far greater activity than those that terminated in apiperidine ring. Thus, Tx-38 and Tx-51 possess little or no activitywhen compared with the significant activities of Tx-37 and Tx-50 againstall tumor lines. Modification of other components of the molecule,however, such as insertion of the hydroxyl moiety at position 13 ofTx-38 (Tx-67) often reduced or eliminated these differences; in thiscase by greatly enhancing its activity.

The preceding description of specific embodiments of the presentinvention is not intended to be a complete list of every possibleembodiment of the invention. Persons skilled in this field willrecognize that modifications can be made to. the specific embodimentsdescribed here that would be within the scope of the present invention.

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What is claimed is:
 1. A method of synthesizing a benzylic ketonecompound, comprising the step of reacting a benzylic methylenehydrocarbon compound that comprises at least two rings with a metalbismuthate in the presence of an acid.
 2. The method of claim 1, wherethe acid is acetic acid.
 3. The method of claim 1, where the acid issulfuric acid.
 4. The method of claim 1, where the reaction takes placein the presence of an organic solvent.
 5. The method of claim 3, wherethe organic solvent is acetone.
 6. The method of claim 1, where thebenzylic methylene hydrocarbon compound comprises from 10-50 carbonatoms.